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Abstract

Stress-related cardiomyopathies can be observed in the four following situations:
Takotsubo cardiomyopathy or apical ballooning syndrome; acute left ventricular dysfunction
associated with subarachnoid hemorrhage; acute left ventricular dysfunction associated
with pheochromocytoma and exogenous catecholamine administration; acute left ventricular
dysfunction in the critically ill. Cardiac toxicity was mediated more by catecholamines
released directly into the heart via neural connection than by those reaching the
heart via the bloodstream. The mechanisms underlying the association between this
generalized autonomic storm secondary to a life-threatening stress and myocardial
toxicity are widely discussed. Takotsubo cardiomyopathy has been reported all over
the world and has been acknowledged by the American Heart Association as a form of
reversible cardiomyopathy. Four "Mayo Clinic" diagnostic criteria are required for
the diagnosis of Takotsubo cardiomyopathy: 1) transient left ventricular wall motion
abnormalities involving the apical and/or midventricular myocardial segments with
wall motion abnormalities extending beyond a single epicardial coronary artery distribution;
2) absence of obstructive epicardial coronary artery disease that could be responsible
for the observed wall motion abnormality; 3) ECG abnormalities, such as transient
ST-segment elevation and/or diffuse T wave inversion associated with a slight troponin
elevation; and 4) the lack of proven pheochromocytoma and myocarditis. ECG changes
and LV dysfunction occur frequently following subarachnoid hemorrhage and ischemic
stroke. This entity, referred as neurocardiogenic stunning, was called neurogenic
stress-related cardiomyopathy. Stress-related cardiomyopathy has been reported in
patients with pheochromocytoma and in patients receiving intravenous exogenous catecholamine
administration. The role of a huge increase in endogenous and/or exogenous catecholamine
level in critically ill patients (severe sepsis, post cardiac resuscitation, post
tachycardia) to explain the onset of myocardial dysfunction was discussed. Further
research is needed to understand this complex interaction between heart and brain
and to identify risk factors and therapeutic and preventive strategies.

Introduction

Neurocardiology has many dimensions, namely divided in three categories: the heart's
effects on the brain (i.e., embolic stroke); the brain's effects on the heart (i.e.,
neurogenic heart disease); and neurocardiac syndromes, such as Friedreich disease
[1]. The present review will focus on the nervous system's capacity to injure the heart.
The relationship between the brain and the heart, i.e., the brain-heart connection,
is central to maintain normal cardiovascular function. This relationship concerns
the central and autonomic nervous systems, and their impairment can adversely affect
cardiovascular system and induce stress-related cardiomyopathy (SRC) [2]. Even if it is unclear whether myocardial adrenergic stimulation is the only pathophysiological
mechanism associated with SRC, enhanced sympathetic tone inducing endogenous catecholamine's
stimulation of the myocardium was always reported [3].

The first description of suspected SRC was reported by W.B. Cannon in 1942 cited by
Engel et al. [4] who published a paper entitled "Voodoo death," which reported anecdotal experiences
of death from fright. This author postulated that death can be caused by an intense
action of the sympathico-adrenal system. In 1971, Engel et al. collected more than
100 accounts from the lay press of sudden death attributed to stress associated with
disruptive life events and provided a window into the world of neurovisceral disease
(i.e., psychosomatic illness).

It is now widely admitted that this autonomic storm, which results from a life-threatening
stressor, can be observed in the four following situations that induce left ventricle
(LV) dysfunction [2]:

Brain-heart connection

Emotional and physical stress can induce an excitation of the limbic system. Amygdalus
and hippocampus are, with the insula the principle brain areas, implicated in emotion
and memory [9,10]. These areas play a central role in the control of cardiovascular function [9,10]. Their excitation provokes the stimulation of the medullary autonomic center, and
then the excitation of pre- and post-synaptic neurons leading to the liberation of
norepinephrine and its neuronal metabolites [11]. Adrenomedullary hormonal outflows increase simultaneously and induce the liberation
of epinephrine. Epinephrine released from the adrenal medulla and norepinephrine from
cardiac and extracardiac sympathetic nerves reach heart and blood vessel adrenoreceptors
[1,9,10]. The occupation of the cardio-adrenoreceptors induces catecholamine toxicity in the
cardiomyocytes [11].

Wittstein et al. compared plasma catecholamine levels in patients with SRC to those
observed in patients with Killip class III myocardial infarction [3]. They reported a neurally induced exaggerated sympathetic stimulation in patients
with SRC [3]. Thus a significant increase in plasma epinephrine, norepinephrine, dihydroxyphenylalanine,
dihydroxyphenylglycol, and dihydroxyphenylacetic acid was observed and was consistent
with the presence of enhanced catecholamine synthesis, neuronal reuptake, and neuronal
metabolism, respectively [3] (Table 1). A significant increase in neuropeptide Y, which is stored in postganglionic sympathetic
nerves, was observed in patients with SRC. By contrast the increase in plasma levels
of metanephrine and normetanephrine, which are extra neuronal catecholamine metabolites,
was within a similar range to that observed in Killip class III myocardial infarction
patients [3]. This finding suggests that cardiac toxicity was mediated more by catecholamines
released directly into the heart via neural connection than by those reaching the
heart via the bloodstream.

The mechanisms underlying the association between this generalized autonomic storm
secondary to a life-threatening stress and myocardial toxicity are widely discussed.
Three mechanisms have been reported. Some authors have suggested that multivessel
epicardial coronary artery spasm could supervene, but angiographic evidence of epicardial
spasm was not reported by Wittstein et al. [3]. Coronary microvascular impairment resulting in myocardial stunning was suspected
by some authors [12]. The most widely accepted mechanism of catecholamine mediated myocardial stunning
is direct myocardial toxicity [13]. Catecholamines can decrease the viability of cardiomyocytes through cyclic AMP-mediated
calcium overload and oxygen-derived free radicals [14]. This hypothesis was sustained by the myocardial histological changes observed in
heart from patients suffering from SRC [1]. These histological changes are the same that those observed following high doses
catecholamine infusion in animals. These changes differ from those observed in ischemic
cardiac necrosis. Contraction band necrosis, neutrophil infiltration, and fibrosis
reflecting high intracellular concentrations of calcium are generally observed [1]. It is now generally assumed that this calcium overload produces the ventricular
dysfunction in catecholamine cardiotoxicity. The low incidence of the onset of these
SRC and their description frequently reported in postmenopausal women suggested the
possibility of a genetic predisposition [15,16]. Thus, Spinelli et al. evaluated the incidence of common polymorphisms of beta 1
and beta 2 adrenergic receptors, the Gs to which the receptors are coupled and GRK5
which desensitizes them [16]. They observed that the GRK5 Leu41 polymorphism was significantly more common in
SRC than in a control group and suggested that this polymorphism was associated with
an enhanced beta adrenergic desensitization which may predispose to cardiomyopathy
caused by repetitive catecholamine surges [15,16].

Stress related cardiomyopathies

Takotsubo cardiomyopathy or apical ballooning syndrome

Japanese authors reported in the nineties the first cases of reversible cardiomyopathy
precipitated by acute and severe emotional stress in postmenopausal women [11,17-20]. This SRC was characterized by the onset of an acute coronary syndrome associated
with a specific and reversible apical and wall motion abnormality despite the lack
of coronary artery disease [11]. Initially, this syndrome was given the name Takotsubo cardiomyopathy and was secondarily
referred to as the apical ballooning syndrome and broken heart disease [11,17-20]. The name Takotsubo was taken from the Japanese name for an octopus trap, which mimics
the typical apical ballooning aspect of the left ventricle during the systole (Figure
1). Takotsubo has been reported all over the world and has been acknowledged by the
American Heart Association and the American College of Cardiology as a form of reversible
cardiomyopathy [21,22]. It has been estimated that 4-6% of women presenting with acute coronary syndrome
suffered from Takotsubo [21].

Figure 1.The name Takotsubo was taken from the Japanese name for an octopus trap, which mimics
the typical apical ballooning aspect of the left ventricle during the systole.

Usually seen in postmenopausal women, the clinical presentation of Takotsubo is similar
to that of an acute coronary syndrome with typical chest pain and ECG abnormalities.
Reported emotional stress included for example death of a family member, traffic road
accidents, financial loss, and disasters, such as earthquakes [5,23,24]. In some patients, no clear precipitating factor can be identified. ST segment elevation
on the ECG was observed in the majority of cases (Figure 2). Twenty-four to 40 hours later, T wave inversion supervened and q waves were seen
in one third of the patients. Thus, there are no ECG criteria to discriminate between
Takotsubo and acute myocardial infarction [5,23,24]. The elevation in troponin is very limited far from the huge increase observed during
myocardial infarction. A very low incidence of in hospital mortality was reported,
and heart failure, cardiogenic shock, and ventricular arrhythmias are observed in
a minority of patients [11,17,23,25].

Typically, echocardiography showed apical and midventricular wall motion abnormalities
and hyperkinesis of the basal myocardial segments [2]. These wall motion abnormalities did not correspond to a single epicardial coronary
distribution. Apical and midventricular wall motion abnormalities can induce a dynamic
obstruction in the LV outflow associated with a systolic anterior motion of the mitral
leaflet.

Figure 3.Left ventricle angiography during diastole (A) and systole (B) showing apical and
mid ventricular wall motion abnormalities and hyperkinesis of the basal segment (arrow). MRI in long axis showing that the akinetic regions are hypoenhanced and dark suggesting
the presence of viable myocardium (C). Reference after an acute myocardial infarction showing hyperenhancement indicative
of necrosis. From reference (3) with permission.

Many morphological LV variants of Takotsubo have been reported: isolated midventricular
and basal dysfunction with apical sparing, isolated basal hypokinesis, named inverse
Takotsubo [11,26]. The reason for this noncoronary distribution of the segmental wall motion abnormalities
was unknown and often related to differences in myocardial autonomic innervation and
adrenergic stimulation [2,3,18].

Patients with suspected and/or proved Takotsubo must be monitored in intensive care.
Because massive catecholamine release was observed in Takotsubo-induced stunned myocardium,
beta agonists and vasopressors might be avoided whenever possible even in acute circulatory
failure and mechanical circulatory support preferred if necessary. Sympathetic activation
suggested the use of beta blocker therapy as soon as LV failure was corrected. The
presence of a dynamic obstruction in the LV outflow precluded the initiation of an
angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or diuretic
treatment because of a possible potentiation. Anticoagulation with heparin was required
to prevent left ventricle thrombus formation [18,24,27].

Echocardiographic examination will be regularly performed after hospital discharge
to evaluate the resolution of LV dysfunction, which is complete in the majority of
the patients after 1 to 3 months. A favorable prognosis has been widely reported in
the more recent literature [23].

Acute LV dysfunction associated with subarachnoid haemorrhage

ECG changes and LV dysfunction occur frequently after subarachnoid hemorrhage and
ischemic stroke. This entity, referred as neurocardiogenic stunning, was called neurogenic
SRC [2]. Four independent predictors of neurogenic SRC have been reported previously: severe
neurologic injury, plasma troponin increase, brain natriuretic peptide elevation,
and female gender [28]. The diagnosis of neurogenic SRC was associated with the potential onset of fatal
arrhythmias and an increased risk of cerebral vasospasm. QT interval prolongation,
ST segment elevation, and symmetrical T-wave inversion associated with an increase
in cardiac troponin were observed in approximately two thirds of patients with severe
subarachnoid hemorrhage [2]. As in the case of Takotusbo, neurogenic SRC often is difficult to distinguish from
acute myocardial infarction. A slight increase in cardiac troponin and the onset of
noncoronary distributed wall motion abnormalities suggest more a neurogenic SRC than
an acute myocardial infarction.

Echocardiography shows hypokinesis involving basal and midventricular portion of the
left ventricle, i.e., inverse Takotusbo. These findings are more usual than those
observed in patients suffering from Takotusbo. Bybee and Prasad have suggested an
algorithm for the evaluation of patients with subarachnoid haemorrhage and LV dysfunction
associated with ECG abnormalities [2]. Similarities exist between Takotusbo and neurogenic SRC, which are both catecholamine-mediated.
This suggests the existence of an overlap between these two entities [3]. Neurogenic SRC also was reported in patients with ischemic stroke and severe head
trauma.

LV dysfunction has been reported in the case of endogenous or exogenous over production
of catecholamines. Pheochromocytoma is a rare neuroendocrine tumor located in the
adrenal medulla that secretes catecholamines and particularly norepinephrine. Many
case reports have suggested the onset of reversible LV dysfunction mimicking neurogenic
SRC and rarely Takotusbo [7,26]. This LV dysfunction was reported during the catecholamine crisis and generally resolved
after the surgical procedure [7,26]. Some case reports suggested that the administration of inhaled and/or intravenous
exogenous catecholamines in patients with severe asthma and bronchospasm could be
involved in the onset of transient neurogenic SRC [29]. Intracellular myocytes calcium overload due to catecholamine enhancement has been
observed in myocardial biopsy specimens [30].

Acute LV dysfunction in the critically ill

Acute LV failure occurs in approximately one-third to one-half of critically ill hospitalized
patients. As reported by Chockalingam et al., determination as to whether the LV dysfunction
is the cause, effect, or a coincidental finding has to be made and revisited periodically
[8]. One of the most widely observed findings in critically ill patients is the onset
of a global LV dysfunction. In patients with hemodynamic instability and acute circulatory
failure, routine echocardiography is increasingly performed to exclude valvular heart
disease, pericardial effusion, and acute coronary syndrome- related regional wall
motion abnormalities.

If a previously undiagnosed dilated cardiomyopathy is excluded, global LV dysfunction
can be partly explained by a relative contribution of direct catecholamine myocardial
toxicity in the following situations: tachycardia-induced cardiomyopathy, hypertensive
crisis, sepsis, multiorgan dysfunction, and postcardiac arrest syndrome. In these
situations, a high incidence of myocardial injury assessed by cardiac troponin I levels
was demonstrated despite the lack of acute coronary syndromes on admission to the
intensive care unit [31,32]. Quenot et al. demonstrated that this myocardial injury was an independent determinant
of in-hospital mortality even when adjusted for the SAPS II score [32].

Tachycardia-induced cardiomyopathy

Tachycardia-induced cardiomyopathy has been defined as a global systolic LV dysfunction
secondary to atrial or ventricular tachyarrhythmias that reversed with rhythm control
[33,34]. Studies in animals have suggested that the progression and the severity of heart
failure were linked to the cadence of the heart rate, the duration of the tachycardia,
and its cause. Thyroid dysfunction, dyskaliemia, hypoxia, and beta1-cardiac receptor
stimulation may exacerbate this catecholamine storm. LV function normalized in a few
days to weeks after the reduction of arrhythmias [33,34].

Sepsis and septic shock

Myocardial dysfunction, which is characterized by transient biventricular impairment
of myocardial contractility, is commonly observed in patients suffering from severe
sepsis and septic shock [37,38]. LV dysfunction has been associated with the elevation of cardiac troponin levels
and indicated a poor prognosis in septic critically ill patients [8,31,32,37,39]. This elevation of the troponin levels occurred in the absence of flow limiting coronary
artery disease. The transient increase in the troponin levels was probably the consequence
of a loss of cardiomyocytes membrane integrity with a subsequent troponin leakage
[8,31,32,37,39]. The mechanisms responsible for increase troponin levels and LV dysfunction are not
clearly understood. The implication of systemic inflammatory response with the liberation
of tumor necrosis factor alpha (TNF alpha) and other cardiosuppressive cytokines,
such as interleukin-6, has been previously reported [8,31,32,37,39]. Histopathological studies in patients with LV dysfunction and septic shock revealed
contraction band necrosis previously reported in case of sympathetically mediated
myocardial injury [40]. Moreover during severe sepsis, oxidative stress and oxygen free radicals could inactivate
catecholamine by an enhancement of their transformation in adrenochromes [41]. The production of adrenochromes explains the loss of the vasoconstrictive effect
of endogen and exogen catecholamines [41]. It also could partly explain myocardial toxicity and troponin liberation due to
the loss of integrity of the membrane of cardiomyocytes [40]. This deactivation of the catecholamines suppresses their role in the inhibition
of TNF alpha production, which is a well-known cardiosuppressive cytokine.

By contrast, some authors consider sepsis-induced myocardial depression an adaptative
and at least partially protective process [42,43]. They have suggested that the myocardial depression was the consequence of the attenuation
of the adrenergic response at the cardiomyocyte level due to down-regulation of the
beta adrenergic receptors and depression of the postreceptor signaling pathways [42,43]. This hibernation-like state of the cardiomyocytes during severe sepsis was probably
enhanced by neuronal apoptosis in the cardiovascular autonomic centers and by inactivation
of catecholamines secondary to the production of reactive oxygen species by oxidative
stress [44]. This physiopathological approach is reinforced by the potential harmful effect of
all strategies designed to enhance oxygen delivery above supranormal values by inotropes
and vasoconstrictors [45].

Thus, to keep adrenergic stimulation of the heart at the minimum level, some recently
published papers suggested a place for beta-blockers to favor the enhancement of the
decatecholaminization in septic critically ill patients [42,43,46]. Obviously, the titration of an adequate dosage of beta-blockers for these hemodynamically
unstable patients is difficult to find during the acute phase. However, as in patients
with SRC, the administration of beta-blockers as soon as possible after stabilization
of the circulatory failure might be suggested or at least investigated in prospective,
randomized, clinical studies [42,43,46]. Recent data suggest that beta-blockers exert favorable effects on metabolism, glucose
homeostasis, and cytokine expression in patients with severe sepsis [47]. It has been reported that septic patients hospitalized in critical settings, previously
treated with beta-blockers, have a better outcome [37,42,43,46,47].

Postcardiac arrest myocardial dysfunction

Prengel et al. reported that severe stress, such as that occurring with cardiac arrest
and cardiopulmonary resuscitation, activates the sympathetic nervous system and causes
a rise in plasma catecholamine concentrations, which could play a role in the onset
of post cardiac arrest myocardial dysfunction [48]. This postcardiac arrest myocardial dysfunction contributes with postcardiac arrest
brain injury to the low survival rate after in- and out-of-hospital cardiac arrest
[48,49]. However, this myocardial dysfunction is responsive to therapy and reversible, suggesting
a stunning phenomenon rather than a permanent and irreversible myocardial injury (i.e.,
myocardial infarction) [50].

The time to recovery appeared to be between 24 and 48 hours and complete for a wide
majority of the patients. Laurent et al. reported that cardiac arrest survivors have
reduced cardiac output 4 to 8 hours later [50]. Cardiac output improved substantially by 24 hours and almost returned to normal
by 72 hours in patients who survived out-of-hospital cardiac arrest. Using multivariate
analysis, Laurent et al. demonstrated that the amount of epinephrine used during cardiopulmonary
resuscitation predicted the occurrence of hemodynamic instability [50]. These results confirm experimental data that suggest that epinephrine potentiates
myocardial dysfunction after resuscitation [51]. Previous clinical studies suggest that high doses of epinephrine infused during
resuscitation may alter the cardiac index after return of spontaneous circulation
and could be an independent predictor of mortality [52]. Many experimental studies reported that epinephrine, when administered during cardiopulmonary
resuscitation, significantly increased the severity of post resuscitation myocardial
dysfunction as a consequence of its beta1-adrenergic actions [50-52]. This result was associated with significantly greater postresuscitation mortality.
Thus, it would be appropriate to reevaluate epinephrine as the drug of first choice
for cardiac resuscitation.

In conclusion, SRC can occur after an acute physical or psychological stress, subarachnoid
hemorrhage, pheochromocytoma crisis, acute medical illness, such as severe sepsis,
and after the administration of exogenous catecholamine administration. The presence
of contraction band necrosis in the myocardial biopsy specimen suggests a catecholamine-mediated
mechanism even if other pathophysiological mechanisms have been suggested. Further
research is needed to understand this complex interaction between heart and brain
and to identify risk factors and therapeutic and preventive strategies.

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myocardial infarction: a report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002
Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial
Infarction) developed in collaboration with the American College of Emergency Physicians,
the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic
Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation
and the Society for Academic Emergency Medicine.

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Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure
and Transplantation Committee; Quality of Care and Outcomes Research and Functional
Genomics and Translational Biology Interdisciplinary Working Groups; and Council on
Epidemiology and Prevention.